The neurotransmitter serotonin (5-HT) has been linked to the pathogenesis of depression, a relatively common disorder with significant morbidity and mortality and to the mechanism of action of antidepressant therapies. Pharmacologic "challenge" paradigms offer the opportunity to study 5-HT systems by measuring physiologic response, usually hormone release, to a specific manipulation of 5-HT activity. Many 5-HT challenge tests may not be specific for 5-HT systems and can provoke stress responses. A new 5-HT challenge test, utilizing IV administration of the 5-HT uptake inhibitor chlorimipramine, may serve as a useful tool for studying the role of 5-HT in depression and its treatment. Low dose IV chlorimipramine (CMI) leads to an increase in plasma prolactin levels in normal volunteers without appreciable side effects and without affecting stress sensitive hormones such as growth hormone and norepinephrine. Results from a pilot study suggest that depressed patients have an altered hormonal response pattern to this "chlorimipramine challenge". In this study, the neuroendocrine response to the IV CMI "challenge" will be studied in 40 medication-free depressed patients, and in 40 matched healthy volunteer controls. At timed intervals before and after CMI infusion, we will measure plasma concentrations of hormones whose release in man can be affected by serotonergic stimulation (prolactin, cortisol, ACTH). At the same time we will use symptom rating scales, cardiovascular measurements, and plasma concentrations of other hormones to detect possible nonspecific or stress-related effects. Plasma concentrations of chlorimipramine and its demethylated metabolite will be measured using gas chromatography. The depressed patients will be restudied following completion of a course of treatment with the norepinephrine reuptake inhibitor desipramine. The healthy volunteer controls will also be restudied after the same period of time. Thus we hope to better understand the status of serotonergic systems in depression by comparing the hormonal responsivity to an acute 5-HT reuptake inhibition "challenge" in depressed patients and in healthy control subjects. In addition, by evaluating the effects of desipramine treatment on this index of serotonergic function our understanding of the mode of action of this antidepressant should be advanced.